Nouvelles approches thérapeutiques pour contrer les infections causées par le metapneumovirus humain
|Abstract:||Respiratory infections are a leading cause of morbidity and mortality worldwide. New viruses are constantly discovered and one of them, the human Metapneumovirus (hMPV), was identified in 2001. hMPV causes upper and lower respiratory infections ranging from cold- or flu-like illnesses to more severe and life-threatening infections such as pneumonia and bronchiolitis. hMPV is only second or third to human respiratory syncytial virus in frequency and sometimes as frequent as human influenza viruses in causing respiratory infections. The majority of severe infections caused by hMPV are seen in individuals having the weakest immune system such as young children, elderly and immunocompromised subjects. Many studies tend to demonstrate that severe viral respiratory infection during childhood can lead to asthma development later in life. Unfortunately, physicians have no vaccine or treatment to fight against severe hMPV infections. Genome and protein fonction analyses are offering promising avenues for the development of effective antivirals. Moreover, hMPV pathogenesis has been described in a murine model which now offers a convenient way to evaluate candidate molecules. This PhD project main goal was therefore to design new molecules against hMPV infections. For that matter, two steps of hMPV replication cycle were targeted, i.e., virus entry into the host cell which happens by a fusion mechanism, and viral genome replication inside the infected cell. The first molecule successfully identified is a fusion inhibitor, the HRA2 peptide that showed highly potent activity against hMPV in vitro but also in vivo. The second group of molecules corresponds to small interfering RNAs (siRNAs) targeting genes essential for hMPV replication. RNA interference has been a rapidly growing field since its first description in the 1990’s. Here, we identified two highly effective siRNAs against hMPV in vitro which target the nucleoprotein and phosphoprotein. Evaluation of these siRNAs in a murine model of hMPV infection also showed great possibilities.|
|Document Type:||Thèse de doctorat|
|Open Access Date:||16 April 2018|
|Collection:||Thèses et mémoires|
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